1. Field of the Invention
The present invention relates to a method for treating cerebral vasospasm and/or cerebral ischemia using iron chelators. More particularly, the present invention relates to a method for treating cerebral vasospasm by administering to a patient an iron chelator which is able to cross the blood-brain barrier.
2. Description of Related Art
Although there are several postulated mechanisms for cerebral vasospasm, there is evidence supporting oxyhemoglobin as the principal spasmogen. Furthermore, recent experiments indicate that the binding properties of iron as a catalytic transitional metal play an important role early in the reaction cascade.
During erythrocyte lysis, free iron is released and accumulates in the cerebrospinal fluid (CSF) in the absence of iron binding proteins (e.g., transferrin. Additionally, oxyhemoglobin is released and auto-oxidizes to form methemoglobin and superoxide radicals. Free iron interacts with superoxides in the Fenton reaction and leads to the formation of hydroxyl radicals. Hydroxyl radicals are extremely reactive and initiate several cascade reactions, including lipid peroxidation, that can lead to cellular injury. (Kassell et al, J Neurosurg 73:18-36, 1990)
Limiting the amount of iron available to catalyze the Fenton reaction results in decreased free radical formation. (Al Refaie et al, Blood 80:593-599, 1992) It has been demonstrated that iron chelation with deferoxamine is effective in attenuating vasospasm. (Comair et al, Neurosurgery 32:58-65, 1993; Kontoghiorghes, Indian J Pediatr 60(4):485-507, 1993) Deferoxamine, a chelator of intra- and extracellular iron, is cytoprotective in several models of tissue injury and has been shown to protect against cerebral vasospasm in vivo. (Comair et al, Neurosurgery 32:58-65, 1993; Hamilton et al, Brit J Haem 86:851-857, 1994; Kontoghiorghes et al, Indian J Pediatr 60(4):485-507, 1993) However, although deferoxamine is effective as an iron chelator, it is relatively hydrophilic and thus does not readily cross lipid bilayers. Such hydrophilic compounds are therefore not as effective for treating cerebral vasospasm, because they cannot cross the blood-brain barrier.
Cerebral ischemia, commonly stroke, is one of the largest causes of morbidity and mortality in the United States. In this medical crisis, brain tissue is deprived of blood. In such a situation, the generation of harmful superoxide radicals may be responsible for a significant amount of damage to brain tissue. Effective suppression of these harmful radicals may protect against at least some of the nerve cell damage encountered in stroke patients.
Therefore, in view of the aforementioned deficiencies attendant with prior art methods of treating cerebral vasospasm and cerebral ischemia, it should be apparent that there still exists a need in the art for method for such treatment.